1. Field of the Invention
This invention relates to vascular catheterization therapy techniques, and particularly to an improvement in transcatheter arterial embolization (TAE) treatment of solid tumors.
2. Brief Description of the Prior Art
Vascular catheterization techniques have improved greatly in recent years and have evolved from their original use in diagnosis to include therapeutic applications as well. One area of such therapeutic uses is therapeutic embolization, with several reports of successful use of embolization for treating malignant tumors.
Transcatheter arterial embolization (TAE) of abdominal tumors, particularly hepatic and renal tumors, has become an integral part of their therapy. For background regarding the use of TAE in treatment of hepatic tumors, see Chuang et al, Semin. Roentgenol., 16: 13-25(1981); Chuang et al, Radiology, 133: 611-614(1979); Chuang and Wallace, Cardiovasc. Intervent. Radiol., 3: 256-267(1980); and Wallace et al, Radiology, 138: 563-570(1981). See also, Wheeler et al, Br. Med. J. [Clin Res], 2: 242-244(1979) and Clouse et al, Radiology, 147: 407-411(1983). Regarding TAE treatment of renal cell carcinoma, see Goldstein et al, Am. J. Radiol., 123: 557-562(1975) and Hlava et al, Radiology, 121: 323-329(1976).
TAE is regarded as particularly effective for hepatocellular carcinomas. Yamada et al, Radiology, 148: 397-401(1983) reports the use of TAE in over a hundred cases of unresectable hepatomas. A vascular catheter was inserted into the hepatic artery that fed the tumor and used to feed a gelatin sponge block impregnated with antineoplastic agent and a contrast medium. Care was required to prevent the backflow of pieces of the sponge block into proximal arteries. See also, Katsushima et al, Radiology, 174: 747-750(1990).
GELFOAM.RTM. particles are readily available in whatever size is needed and are usually used as the embolic material. However, GELFOAM.RTM. particles occlude the major feeding vessels but not the minute tumor vessels. The response to this has been attempts to use other embolic materials such as small IVALON.RTM. particles and ferropolysaccharides. See Chuang et al, Am. J. Radiol., 136: 729-733(1981) and Sako et al, Invest. Radiol., 17: 573-582(1982), respectively.
Ohishi et al, Radiology, 154: 25-29(1985) reports the use of TAE in treatment of hepatocellular carcinoma cases where surgical intervention was considered impossible. GELFOAM.RTM. particles were introduced as the embolic material into the catheter following angiographically controlled infusion of an ETHIODOL.RTM.-anticancer agent emulsion via the appropriate hepatic artery. This combined therapy is said to have the dual effects of occlusion of peripheral vessels, including tumor vessels, by the ETHIODOL.RTM.-anticancer agent emulsion, followed by embolization of the main feeding vessels with Gelfoam particles.
Thus, TAE has been developed as a therapeutic technique for permanent occlusion of the blood supply to solid tumors, such as in the reports identified above, and often also as a means for delivering antineoplastic agents to the tumor site as emulsions or impregnated in the occluding material.
Separate from the progress in the above field, compounds such as streptokinase and tissue-type plasminogen activator (TPA) have been used in the treatment of coronary artery occlusions. One of the major problems encountered has been the tissue damage occurring after reperfusion has been established. Recent evidence suggests that oxygen-derived free radicals may be abundantly produced in ischemic tissues, accounting for at least part of the damage that results. Oxygen-derived free radicals include the superoxide anion, produced by the one-electron reduction of dioxygen, the hydroxyl radical and singlet oxygen.
Ischemia, by itself, will ultimately produce tissue death if it is sufficiently severe and prolonged. However, much of the injury may occur during reperfusion, rather than during the period of hypoxia. Occluded blood does not contain free radicals. Occluded blood contains oxygen which is converted by hypoxanthine and xanthine oxidase to oxygen-derived free radicals after reperfusion. The mechanism and effects of the sequence of reactions that produce the superoxide and other oxygen-derived cytotoxic species is reviewed in McCord, N. Eng. J. Med., 312: 159-163(1985).
Thus, their removal has become the focus of study leading to the use of compounds such as superoxide dismutase or the avoidance of streptokinase or TPA as emergency therapeutic agents altogether.
When generated in the media surrounding cells in tissue culture, oxygen species, particularly hydrogen peroxide, have been reported to lyse tumor cells. See, Simon et al, J. Biol. Chem., 256: 7181-7186(1981); Granger et al, J. Clin. Invest., 65: 357-370(1980); Nathan et al, J. Exp. Med., 149: 84-99(1979); Clark and Klebanoff, J. Exp. Med., 141: 1442-1447(1975); and Clark et al, Blood, 45: 161-170(1975). However, it is noteworthy that Simon et al conclude that hydrogen peroxide is the agent responsible for cell death and that no direct effect was attributable to superoxide anions, hydroxyl radicals or singlet oxygen.
TAE has met with some success in the treatment of solid tumors and some researchers have investigated the effect of oxygen species on tumor cells. However, the above work has not brought these areas of clinical treatment and experimental investigation together, particularly in any way for their combined use in a clinical regimen for treating solid tumors.